For the primary endpoint of progression-free survival (PFS), the median PFS in a modified intention-to-treat analysis was 25 months among those who continued to receive standard administration of ICIs after 6 months of therapy versus 21.9 months for patients who went on to receive ICIs every 3 months (HR 1.35, 96.16% CI 0.90-2.04, P=0.0635), reported Gwenaëlle Gravis, MD, of the Institut Paoli-Calmettes in Marseille, France.
Moreover, the study was stopped early because of an "unexpected overall survival imbalance" favoring the standard treatment arm that was "clinically concerning," Gravis said at the European Society for Medical Oncology annual congress in Madrid.
Specifically, there were more deaths among patients who received de-escalated ICI therapy versus standard treatment (19.9% vs 10.5%, HR 2.04, 95% CI 1.08-3.85, P=0.0286).
This occurred even though the trial's prespecified PFS futility threshold was not crossed.
The available data from the trial "do not allow conclusions regarding inferiority or noninferiority of the 12-week ICI strategy," Gravis said. However, the results also "cannot support the implementation of 12-week ICI in patients responding after initial therapy."
"Further studies are needed to better define effective ICI de-intensification strategies," she concluded.
The trial was designed with the hypothesis that a reduced dose intensity of immunotherapy could not only be as effective as standard treatment in terms of prevention of disease progression, but could also have a positive effect by reducing the costs associated with treatment and toxicity and improving patients' quality of life.
In this study, noninferiority was met if the upper bound of the confidence interval for the HR was ≤1.30 -- a margin that led invited discussant Jarushka Naidoo, PhD, MPH, of the Beaumont RCSI Cancer Centre in Dublin, to ask whether clinicians should be comfortable with a 30% increase in the risk of progression in order to reduce treatment intensity.
She also pointed out that the study involved 14 tumor types, with the most common being lung cancer, urothelial carcinoma, and renal cell carcinoma, with the efficacy of the intervention varying widely across those cancers. For example, patients with lung and bladder cancers were at higher risk with the reduced-intensity approach, while those with renal cell carcinoma and head and neck cancer appeared to benefit.
Naidoo said those subset results should be interpreted "cautiously," since all confidence intervals crossed the noninferiority boundary and overlapped it.
Furthermore, she suggested the pan-tumor approach to noninferiority "is unlikely to have been the ideal trial ... given the heterogeneity of immunotherapy responses and the pharmacology of how these treatments work. We need to focus on specific tumors and settings in which we have homogeneous outcomes."
Naidoo noted that the results of the study might lead to the question of whether interval immunotherapy should be abandoned as a means of de-escalation in clinical trials, but added that there might be a better way of evaluating it.
De-escalation could be pursued with a "range of strategies," using dynamic trial designs that allow for the testing of multiple intervals, she said. For example, the REFINE-Lung trial is investigating whether reduced pembrolizumab (Keytruda) dose frequency (every 9, 12, 15, or 18 weeks versus every 6 weeks) is safe and effective for patients with non-small cell lung cancer after 6 months of standard treatment.
"The field of immunotherapy de-intensification is absolutely wide open, and we need to continue exploring dose, duration, interval, and omission," Naidoo urged. "But make sure that our questions are based on biology, pharmacology, as well as clinical principles."
Overall, the MOIO study randomized 340 patients -- 308 in the modified intention-to-treat analysis -- with locally advanced/metastatic solid tumors who had previously achieved a complete or partial response to 6 months of ICI therapy. Median follow-up was about 19 months.
Most of the patients were men, median age was about 70 years, and the majority had metastatic disease. At the time of randomization, most patients had a partial response to therapy (67.1% in the standard group and 70.5% in the reduced group), about three-quarters had received one line of treatment, and about 80% were on PD-1 inhibitors.
A surprising finding from the study was that there was no substantial difference in adverse events between groups. Grade ≥3 treatment-related adverse events occurred in 10.5% of patients in the standard ICI group and 9.5% in the reduced ICI group, and treatment discontinuation occurred in 7% and 4.8%, respectively.
Disclosures
Gravis reported relationships with Novartis, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Pfizer, Astellas, Eisai, Johnson & Johnson, and MSD.
Naidoo reported relationships with AstraZeneca, Bristol Myers Squibb, Roche/Genentech, Amgen, Summit Therapeutics, Arcus Biosciences, Zymeworks, NGM Pharmaceuticals, Bayer, Regeneron, Takeda, Pfizer, Elevation Oncology, AbbVie, Kaleido Biosciences, Ilios Biopharmaceuticals, and Daiichi Sankyo.
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